close

Вход

Забыли?

вход по аккаунту

?

Macrocycles by Intramolecular Diels-Alder ReactionЧRegioselective Synthesis of Anthracycline Precursors.

код для вставкиСкачать
4 by base-induced H I D exchange in tetrahydrofuran
(THF), was investigated (KOt-C,H,, DzO-THF, room temperature, 16 h, yield 19%). The deuterium content quoted
in Scheme 2 derives from the 'H- and 'H-NMR spectra.
After partial thermolysis of 11,2-Dz]-4 (llO"C, 140 min,
conversion: 50%), the content and position of the deuterh m atoms in the recovered educt remain unchanged. According to the 'H- and 'H-NMR analyses, the main product consists of equal amounts of the regioisomers trans[1,2-Dz]-5 and trans-[2,3-Dz]-5.
The surprising formation of trans-5 from the cis-configurated dihydropyrazole 4 can be explained as follows: After
the valence-isomerization 4 + 1, N,-cleavage starts to take
place from the exo-conformation of 1 shown in Scheme 2;
this conformation of 1 is undoubtedly thermodynamically
preferred over the corresponding endo-conformation. The
structure of the likely diradical intermediates 8 and/or 2
resembles that of the homotropylium ion, and favors ringclosure to the trans-configurated bicyclo[6.1.O]nonatriene
system. For formation of the cis-bicyclo[6.1.O]nonatriene,
the intermediate must exist in the endo-conformation. Ring
inversion obviously competes only to a very limited extent,
if at all, with the ring-closure reaction. From the deuterium
labeling experiment it can be concluded that the ring-closure between C-9 and C-1 proceeds at the same rate as that
between C-9 and C-7. This finding can hardly be reconciled with the diazenyl diradical 8 as intermediate for the
ring-closure. For the rear attack on the C atom bearing the
diazenyl radical previously discussed in the literature, a
preferred ring-closure between C-9 and C-7 would be expected. The experimental result, however, rather requires
an intermediate having the symmetry properties of the N2free diradical 2. The observation that the cis-configuration
is preserved during the "walk" rearrangement in the cis-bicyclo[6.1.0]nonatriene system rules out the participation of
a diradical intermediate of type 2 in this process.
Received: September 16, 1983 [Z 552 IE]
revised: November 14, 1983
German version: Angew. Chem. 96 (1984) 78
[I1 Review: F.-G. Klarner, F. Adamsky, Chem. Eer. 116 (1983) 299. F.-G.
Klamer, Top. Stereochem. 15, in press.
[21 A. Calatroni, R. Gandolfi, Heterocycles 14 (1980) 1115.
[31 'H-NMR(250 MHz, CDC13, TMS): 1 (-23°C): 6=1.22, 1.50 (s, 2CH3);
2.47 (d*, 8-H, J1,8=7.6 Hz); 5.52 (dd*, 1-H, J1,2=6.3 Hz); 5.64-5.79,
5.88-6.20 (m, 2-H to 7-H).-4: 6=1.10, 1.61 (s, 2CH3); 2.48 (m, 8-H,
J1,a=5.5 Hz, J2,8=1.0 Hz, J7,8=6.3 Hz); 2.67 (m, 7-H, J1,,=1.0 Hz,
J2.7-9.3 HZ,J6,7=5.1 HZ); 3.05 (m, 2-H, J1,2=3.0 Hz, J2,3=3.0 Hz); 5.16
(m, 1-H); 5.47 (dd*, 6-H, J5,6=9.8 Hz); 5.73 (m, 3-, 5-H); 5.86 (m, 4-H).trans-5 (c6D6): 6=0.61 (d*, 1-, 8-H, Jl,z=J7,a=1.6 Hz); 1.15 (s, 2CH3);
5.91-6.36 (m, 2-H to 7-H).--The signals marked with an asterisk are
broadened by extensive coupling.
141 Review: G. I. Frey, R. G. Saxton: The Chemistry of Cyclo-octatetraene and
its Deriuatiues, Cambridge University Press, Cambridge (England) 1978,
p. 40ff.
151 a) cis-9,9-Dimethylbicyclo[6.I.O]nona-2,4,6-triene: S. W. Staley, T. J. Henr y , J . Am. Chem. SOC.91 (1969) 1239; b) GC: 70 m glass capillary column,
silicone oil OV 101, temperature 1OO"C, helium as carrier gas. trans-5 is
not entirely stable under the GC conditions; in some analyses it rearranges (up to cu. 3%) to a hydrocarbon which has the same retention time
as trans-1,l-dimethyl-7,7a-dihydroindene.
161 G. Snatzke, H. Langen, Chem. Eer. 102 (1969) 1865.
171 The parent compound trans-bicyclo[6.1.0]nona-2,4,6-trieneis formed,
inter alia, in the photolysis of cis-bicyclo[6.1.0]nona-2,4,6-triene.W.
Grimme, Habilitationsschrift, UniversitXt Koln 1968; G. Masamune, P.
M. Baker, K. Hojo, Chem. Commun. 1969, 1203.
[8] Review: P. S. Engel, Chem. Reu. 80 (1980) 99. For the case of the diazenyl
diradical 8 as an intermediate the rotation about the C8-C9 bond must
be assumed to precede the ring-closure reaction. According to the observed stereoselectivity, conformational processes seem to compete with
the ring-closure reaction to only a minor extent.
74
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
Macrocycles by
Intramolecular Diels-Alder ReactionRegioselective Synthesis of Anthracycline
Precursors**
By Joaquin Tamariz and Pierre Vogel*
The intramolecular Diels-Alder reaction is a powerful
synthetic tool and has been applied widely"]. Usually, the
connective chain between diene and dienophile moieties
consists of three to five atoms; if longer, the intramolecular reactivity and regio- and stereoselectivity decrease. It is
therefore not surprising that this technique has not yet
been widely used for the synthesis of medium-ring and macrocyclic corn pound^^^^^^. We report here an unusual regioand stereoselective macrocyclic synthesis using an intramolecular Diels-Alder reaction. The method suggests a
new approach to the synthesis of anthracycline precursors
such as daun~mycinone[~~.
yJmm
MsV
/
\
\
\
\
i)K
1
4, R = CcHSCO
5,R=H
6,
7,
8,
9,
R = (CH,),OH
R = (CH,),OCOCH=CH,
R = (CH2)$dr
R = (CH,),jOCOCH=CH,
Mesylate 2, derived from 1IS1,furnished phenolate 3
upon treatment with KOtBu. Reaction with benzoyl chloride, followed by oxidation with dichlorodicyanobenzoquinone gave 4 (%yo, m. p. = 148-149°C). Inspection of
simple molecular models indicates that an intramolecular
Diels-Alder addition could be possible if, for example,
acrylic acid were linked to naphthol 5 through a threemembered chain. Transesterification of 4 (KZC03/
CH30H) furnishes 5 (m.p. = 194-195"C, 98%). The corresponding naphthoate generated in tetrahydrofuran (THF)
using NaH reacts with 3-bromopropanol (molar ratio 1 : 1,
70°C, 3 h) to give 6 (m.p.=134-135"C, 96%). Esterification with acrylic acid yields 7 (51.5%). When dilute solutions ( < 8 x l o p 3 M) of 7 in xylene (with or without ZnCI,
or BF3.EtzO) are heated to 140-240°C only polymerization was observed. The failure to observe macrocycle formation with 7 led us to choose a longer connecting chain
between diene and dienophile.
The sodium naphthoate of 5 , generated using NaH in a
mixture of THF and hexamethylphosphoric triamide (1 :2)
reacts with 1,6-dibromohexane (molar ratio 1 :4, O"C, 0.5
h) to yield bromide 8 (75?/0).Treatment with acrylic acid
and 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) (molar ratio
2.2 :2 :1) in benzene (SOOC, 2 h) afforded acrylate 9 as a
[*I Prof. Dr. P. Vogel, Dr. J. Tamariz
Institut de chimie organique, Universite de Lausanne
2, rue de la Barre, CH-1005 L.ausanne (Switzerland)
[**I This work was supported by the Swiss National Science Foundation, the
Commission Fedkale des Bourses, and Hoffmann-La Roche AG, Basel.
0570-0833/84/0101-0074 $02.50/0
Anyew. Chem. lnt. Ed. Engl. 23 (1984) No. I
colorless oil (63%), which polymerizes rapidly in the condensed state. When 9 was diluted in xylene (1.6 x lop3 M)
containing traces of hydroquinone and the solution heated
to 170°C for 23 h, the macrocycle compound 10 was obtained as a homogeneous oil (58% after chromatography
on silica gel) together with unreacted 9 and polymeric material. Characteristic data for compounds 7-10 are summarized in Table 1.
Table 1. Melting points and selected spectroscopic data of compounds 710.
7 : m.p.=109-110°C; UV(CH3CN):A=300(&=3600), 252(48100),218 nm
(45800); 1R (KBr): v=1720, 1595 cm-'; 'H-NMR (CDCI,): 6=8.16, 7.67
7.41 (d. J=8.2 Hz, lH), 7.37 (dd, J=7.4, 8.2 Hz, lH), 6.83 (dd,
( 2 ~ ZH),
,
J = 1.0, 7.4 Hz, 1 H), 6.44 (dd, J = 1.6, 17.6 Hz, 1 H), 6.16 (dd, J = 10.8, 17.6
Hz, 1 H), 5.85 (dd, J = 1.6, 10.8 Hz, 1 H), 5.73, 5.70, 5.32, 5.26, 5.23 (SS, 5H),
4.5 (t, J=6.4 Hz, 2H), 4.26 (t, J=6.0 Hz, 2H), 2.32 (m, 2H). MS (70 ev):
m/z=348 ( M + ,
56), 293 (13), 113 (100).
8 : m.p.=101--102"C: UV (CH,CN): d=302 (&=330), 252 (48000), 218
(44900); IR (KBr): 2950, 1590, 1505 cm-'. 'H-NMR (CDCI,): 6=8.17, 7.66
7.39 (dd, J=2, 8.0 Hz, IH), 7.34 (t, J=8.0 Hz, IH), 6.82 (dd,
( 2 ~ 2H),
,
J=2.0, 8.0 Hz, IH), 5.74, 5.71, 5.32, 5.26, 5.22 (SS, 5H), 4.13 (t, J=6.4 Hz,
2H), 3.44 (t, J=6.6 Hz, ZH), 1.93 (m, 4H), 1.59 (m, 4H); MS (70 ev):
m/z-398 ( M + , 20), 371 ( 4 , 44 (100).
9 : UV (CHKN): 1 = 3 0 2 (&=3400), 252 (44700), 218 (42300); IR (film):
v=2940, 1725 cm-'; 'H-NMR (CDCI,): 6=8.15, 7.65 (2s, 2H), 7.37 (dd,
J = 1.0,7.2 Hz, 1 H), 7.33 (t, J = 7 2 Hz, 1 H), 6.8 (dd, J = 1.0,7.2 Hz, 1 H), 6.40
(dd, J=1.3, 17.2 Hz, l H ) , 6.13 (dd, J=10.5, 17.2 Hz, lH), 5.81 (dd, J=13,
10.5H~,lH),5.73,5.69,5.32,5.26,5.23(5~,1H),5.21(t,J=6.6Hz,2H),4.12
(t, J-6.6 Hz, 2H), 1.95, 1.75, 1.62, 1.52 (4 quintet, J=6.6 Hz, 4 x 2 H ) ; MS
(70 ev): m/z=390 ( M + 7,3 , 335 (25), 236 (100).
10: UV (EtOH): 1 = 3 3 4 (&=420), 317 (700), 292 (sh, 410001, 280 (sh, 5600),
274 (sh, 5700), 252 (24600), 230 (20200); IR (CHCI,): 3010, 2940, 1735, 1600
cm-'; 'H-NMR (CDCI,): 8.03 (s, 1 H, 6-H), 7.51 (s, 1 H, 11-H), 7.33 (dd,
J=7.2, 8.0 Hz, l H , 9-H), 7.29 (dd, J=1.5, 8.0 Hz, l H , 10-H), 6.89 (dd,
J=1.5, 7.2 Hz, l H , 8-H), 5.62 (m, I H , 12-H), 5.60 (m, I H , 5-H), 4.32 (t,
J=5.5 Hz, 2H, H&-OCO), 4.05 (ddd, J=3.4, 5.2, 10.2 Hz), 3.73 (ddd,
J=3.4, 10.2, 11.2 Hz, 2 H , H2C-0), 2.58 (dm, J=18.0 Hz, l H , lp-H), 2.27
(m, 2H, 2-H,4p-H), 1.85-1.33 (m,9H), 1.25 (m, 2H), 0.77 (dddd, J=4.0,6.0,
10.0, 18.0 Hz, 1 H, 3a-H), cf. also text; MS (70 ev): m/z=390 (M+,
Il), 234
(100); MS (CI, CH.,): 391 (M++H).
-
The structure of 10 was determined using 360 MHz 'HNMR spectroscopy (cf. also Table 1). The distinction between the signals of the aromatic protons 6-H and 11-H is
based on NOE measurements. Similarly, the signals of the
bridgehead protons 5-H and 12-H was obtained using
NOE measurements (proximity to 6-H and 11-H, respectively). A homoallylic SJ coupling constant of 1.7 HZ was
measured between lP-H and 5-H. This is somewhat larger
than expected (1-1.4 Hz) for cyclohexenes annelated to 7oxanorbornenes[61and suggests a blocked conformation of
the A-ring with 1P-H in an axial position (Fig. 1). The cou-
Fig. 1. Conformation of the "right part" of 10 (schematic).
pling constants 4J12.H,
1p-H = 0.2-0.3 Hz and
'2-H =
0.2-0.3 Hz were observed, confirming a blocked chair
conformation in which 40-H is equatorial. 2-H couples
with 1p-H and la-H with relatively small vicinal coupling
constants (3-4 Hz); 2-H also couples strongly with 3a-H
Angew. Chem. Int. Ed. Engl. 23 (1984) No. I
(10 Hz) and weakly with 3P-H ( < 1 Hz). The measured
coupling constants between 3a-H and 4p-H (6 or 4 Hz) and
between 3a-H and 4a-H (4 or 6 Hz) are in agreement with
structure 10 and the conformation depicted in Figure 1.
Variation of the concentration of 9 (1-4 x
M) did
not affect the yield of 10, as expected for an intramolecular Diels-Alder addition. Inspection of molecular models
suggests a preferred attack at the endo face, thus requiring
the acrylic ester in 9 to adopt an orientation consistent
with Alder's endo rule. Compound 10 can be viewed as an
eighteen-membered ring ar~sa-lactone['~.
The transformation of tetraene 1 into 10 suggests a new
approach to the total synthesis of anthracycline precursors
involving control of the regiostereoselectivity of the substituents of ring A with respect to those of ring DIs1.Methods
for generating 2 in optically pure form and for stereoselecare being
tive transformation of 10 into daunomy~inone[~]
investigated.
Received September 19, 1983;
revised: November 14, 1983 [Z 554 IE]
German version: Angew. Chem. 96 (1984) 61
CAS Registry numbers:
1, 53011-99-7; 2, 88336-07-6; 3, 88315-90-6; 4, 88315-91-7; 5, 88315-92-8;
5.Na, 88315-98-4; 6, 88315-93-9; 7,88315-94-0; 8,88315-95-1; 9,88315-96-2;
10, 88315-97-3; 3-bromopropanol, 627-18-9; acrylic acid, 79-10-7; 1,6-dibromohexane. 629-03-8.
[I] a) Reviews: R. G. Carlson, Annu. Rep. Med. Chem. 9 (1974) 270; W. Oppolzer, Angew. Chem. 8911977) 10; Angew. Chem. Inf. Ed. Engl. 16 (1977)
10; Synthesis 1978, 793; G. Brieger, J. N. Bennet, Chem. Rev. 80 (1980)
63; R. L. Funk, K. P. C. Vollhardt, Chem. SOC.Rev. 9 (1980) 41; b) K. J.
Shea, S. Wise, L. D. Burke, P. D. Davis, J. W. Gilman, A. C. Greeley, J.
Am. Chem. SOC.104 (1982) 5708; R. K. Boeckman, Jr., S. S. KO, ibid. 104
(1982) 1033; R. K. Boeckman, Jr., T. R. Alessi, ibid. 104 (1982) 3216 and
references cited therein; S. G. Pyne, M. J. Hensel, P. L. Fuchs, ibid. 104
(1982) 5719; W. R. Roush, H. R. Gillis, A. I. KO,ibid. 104 (1982) 2269; M.
Hirama, M. Uei, ibid. 104 (1982) 4251; A. Pelter, B. Singaram, Tetrahedron Left. 23 (1982) 245; D. D. Sternbach, J. W. Hughes, D. F. Burdi, R.
M. Forstot, ibid. 24 (1983) 3295; L. A. Van Royen, R. Mijngheer, P. J. De
Clerq, ibid. 23 (1982) 3283; W. M. Grootaert, P. J. De Clerq, ibid. 23
(1982) 3291; N. S. Isaacs, P. Van der Beeke. ibid. 23 (1982) 2147: S. K. Attah-Potu, G. Gallacher, A. Ser Ng, L. E. B. Taylor, A. G. Alwardand, A.
G. Fallis, ibid. 24 (1983) 677; D. L. Comins, A. H. Abdullah, R. K. Smith,
ibid. 24 (1983) 2711; W. R. Roush, H. R. Gillis, J. Org. Chem. 47 (1982)
4825; M. E. Jung, L. A. Light, ibid. 47 (1982) 1084; B. B. Snider, J. V.
Duncia, ibid. 45 (1980) 3461; S. D. Burke, S. M. Smith Strickland, T. H.
Powner, ibid. 48 (1983) 454.
[2] E. J. Corey, M. Petrzilka, Tetrahedron Lett. 1975, 2537; see also: J. Brokatzky-Geiger, w. Eberbach, ibid. 23 (1982) 4665.
[31. S. J. Bailey, E. J. Thomas, S. M. Vather, J. Wallis, J. Chem. Soc. Perkin
.
Trans. 11983, 851; G. Stork, E. Nakamura, J. Am. Chem. SOC.105 (1983)
5510.
[4] F. Arcamone: Doxorubicin, Academic Press, New York 1981.
[5] L. Tamariz, L. Schwager, J. H. A. Stibbard, P. Vogel, Tetrahedron Lett. 24
(1983) 1497.
[6] C. Mahaim, P. Vogel, Helv. Chim. Acta 65 (1982) 866.
[7] T. G. Bach, Tetrahedron 33 (1977) 3041; G. R. Newkome, J. D. Sauer, J.
M. Roper, D. C. Hager, Chem. Rev. 77 (1977) 513.
[8] For recent examples of the regioselective synthesis of anthracyclinones:
A. V. Rama Rao, K. Bal Reddy, A. R Mehendale, J . Chem. SOC.Chem.
Commun. 1983, 564; R. N. Warrener, P. S. Gee, R. A. Russell, ibid. 1981,
1100; R. K. Boeckmann, Jr., S. H. Cheon, J . Am. Chem. SOC.105 (1983)
4112; H. Sekizaki, M. Jung, J. M. McNamara, Y. Kishi, ibid. 104 (1982)
7372; T . R. Kelly, J. Vaya, L. Ananthasubramanian, ibid. 102 (1980) 5983;
B. A. Keay, R. Rodrigo, Can. J. Chem. 61 (1983) 637; C. E. Coburn, D. K.
Anderson, J. S. Swenton, J. Org. Chem. 48 (1983) 1455; Y. Tamura, A.
Wada, M. Sasho, K. Fukunaga, W. Maeda, Y. Kita, J . Org. Chem. 47
(1982) 4376; J. P. Gesson, J. C. Jacquesy, M. Moudon, Nouv. J. Chimie 7
(1983) 205; S. Terashima, K. Tamoto, Tetrahedron Lett. 23 (1982) 3715
and references cited therein.
[9] See known procedures, e.g.: C. M. Wong, R. Schwenk, D. Popien, T. L.
Ho, Can. J . Chem. 51 (1973) 466; J. S. Swenton, P. W. Raynolds, J. Am.
Chem. Soc. 100 (1978) 6188; M. G. Dolson, B. L. Chenard, J. S. Swenton,
ibid. 103 (1981) 5263; S. Terashima, S.-s. Jew, K. Koga, Tetrahedron Lett.
1978, 4937; F. M. Hauser, S. Prasanna, J. Am. Chem. SOC.103 (1981)
6378; see also 151.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0101-0075 $02.50/0
75
Документ
Категория
Без категории
Просмотров
1
Размер файла
284 Кб
Теги
reactionчregioselective, synthesis, intramolecular, anthracycline, alder, macrocyclic, precursors, diels
1/--страниц
Пожаловаться на содержимое документа